A. Field of the Invention
The present invention relates generally to the fields of neurology and the pharmacotherapy. In particular, the present invention provides methods of improving cognitive deficits which occur following stroke and other conditions which interfere with the brain receiving the necessary blood supply or oxygen.
B. Description of the Related Art
The central nervous system (CNS) is highly vulnerable to ischemic injury. Because the CNS neurons are solely dependent on the glucose and oxygen delivered by the blood (Siesjo et al., 1976), inadequate blood supply or “stroke” can easily trigger degeneration of CNS neurons. Stroke is one of the leading causes of death in Western, as well as, Asian countries. In the U.S., stroke sufferers total 700,000, and 30% of these stroke-afflicted patients die, while another 20-30% become severely and permanently disabled. Current treatments for stroke patients are drug therapies that provide for clot removal and cell survival maintenance. No drugs are currently used for the persistent dementia syndrome subsequent to stroke.
Two major types of drugs have been demonstrated to produce some beneficial effects against stroke. One type of drugs is utilized to ensure continuous blood flow to the CNS after a stroke by dissolving blood clots, and these include the anticoagulants or thrombolytics such as aspirin, heparin, and platelet inhibitors (Schellinger et al., 1997). Another group of drugs, appropriately called “cell maintenance drugs,” is principally used to block neuronal degenerative processes. These drugs are NMDA receptor blockers, calcium channel blockers, caspase inhibitors, protein kinase inhibitors, free radical scavengers, and neurotrophic factors (Endres et al., 1998; Nishino et al., 1998; Wang et al., 1997). The limited efficacy of these drugs is primarily due to the narrow window of rescuing ischemic CNS neurons (Lee et al., 1999).
The unpredictable nature of the majority of stroke cases means that treatment cannot be initiated until the injury becomes apparent. Moreover, identification of the stroke as ischemic or hemorrhagic is critical to the potential benefit of thrombolytic drugs; treatment of a hemorrhagic stroke with thrombolytic drugs could lead to excessive bleeding and may be fatal to the patient. On the other hand, cell maintenance drugs can temporarily support cell integrity, but they may not correct the stroke-induced energy deficit nor block secondary neurodegenerative mechanisms. Thus, thrombolytic and cell maintenance drugs can only promote partial protection or a delay in the onset of degeneration.
Patients who survive acute stroke are left with motor, verbal, cognitive or affective dysfunctions. Unfortunately, a less concerted research effort in the treatment of stroke is provided for rehabilitation of the survivors. Recently, the need for exercise training or a similar physical therapy program for stroke survivors has been shown to aid in recovery of lost motor skills (Dobkin, 1998; Macko et al., 1997), but restoration of cognitive functions in stroke survivors has been less examined.
The problem, however, has been to develop an effective, relatively nontoxic inhibitor for acetylcholinesterase (acetylcholinesterase, EC 3.1.1.7), the enzyme widely accepted as involved in memory functions (Deutsch, 1971; Drachman and Glosser, 1981). Cholinesterase inhibitors, in general, are a relatively toxic compounds because significant inhibition of these enzymes in peripheral tissues are associated with nausea, vomiting, diarrhea, excessive salivation, and other signs of excessive cholinergic activity. In addition there is some evidence that inhibition of butyrylcholinesterase (BchE, E.C. 3.1.1.8), concurrently with acetylcholinesterase (AchE, E.C. 3.1.1.7), potentiates the toxicity of cholinesterase inhibitors in peripheral smooth muscle (Reutter et al., 1987). The ideal cholinesterase inhibitor to be used for the treatment of a chronic disease such as cognitive impairment would, therefore, be selective for the CNS (compared to peripheral tissues), be long acting, and have a high degree of selectivity for acetylcholinesterase (compared to butyrylcholinesterase).
Methanesulfonyl fluoride (MSF) is a long-acting irreversible inhibitor of acetylcholinesterase that shows excellent selectivity for the CNS (Moss et al., 1988; Moss et al., 1985). This selectivity seems to be due, in part, to the irreversible mechanism of action. Recovery from irreversible inhibition is a simple function of the rate of new synthesis of acetylcholinesterase in each tissue. Fortunately, acetylcholinesterase in the brain is resynthesized at a rate much slower than peripheral tissues (Moss et al., 1988; Moss et al., 1985). Therefore, methanesulfonyl fluoride can be used to accumulate up to 80-90% inhibition of rodent and monkey brain acetylcholinesterase with minimum inhibition of peripheral enzyme and without toxicity by using relatively small doses of the drug over a long period of time (Moss et al., 1988; Moss et al., 1985).
Methanesulfonyl fluoride also has high selectivity as an inhibitor of acetylcholinesterase in comparison to butyrylcholinesterase and is much better with regard to this quality than tacrine, metrifonate, and physostigmine which do not show this high degree of selectivity (Pacheco et al., 1995). This may also be one mechanism by which methanesulfonyl fluoride avoids peripheral toxicity. In summary, therefore, methanesulfonyl fluoride is a long-acting, acetylcholinesterase-selective inhibitor that can produce up to 80-90% inhibition in the brain without toxicity.
Despite the research discussed above, there are significant problems in this art in determining whether a potential therapeutic pharmaceutical will be clinically efficacious in humans. The results given below show that treatment with MSF produces functional effects in adult rats subjected to an experimental stroke model.